a prospective, open-label trial of two abc/3tc based regimens in late presenter naïve patients (cd4 <200 cells/µl)

Conditions: HIV Infection

Summary: 1. protocol summary this is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (drv/r) vs abacavir/lamivudine + raltegravir (ral) in antiretroviral therapy naive, hiv+ individuals presenting for care with cd4+ counts \< 200/mm3. 1.1 clinical objectives: primary objective: to compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (drv/r) vs abacavir/lamivudine + raltegravir (ral) in antiretroviral therapy naive, hiv+ individuals presenting for care with cd4+ counts \< 200/mm3. secondary objective: a) to compare immunological response at 48 weeks; b) to determine the safety and tolerability of the 2 regimens. 1.2 study population: 350 in/out patients 1.3 outcome primary endpoint * proportion of patients with hiv rna\<50 copies/ml after 48 weeks secondary endpoints(s) * change in cd4+ cell count from baseline through week 48 * time to virological rebound 1.4 study design: multicentre, parallel group, randomised, open label, non-inferiority study 1.5 treatment regimens: arm a: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) arm b: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day. all drugs have been approved for the treatment of hiv infection. the study population will consist of 350 hiv-positive, hla b5701-negative patients. at baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. randomization will be stratified on the basis of the screening cd4+ cell count (≤100 vs ≥100 cells/µl), to ensure balance across treatments groups 1.7 criteria for safety: adverse events and laboratory assessments. 1.8 statistical analysis: as this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. in case non-inferiority will be met, analyses for superiority will be performed.

1. protocol summary this is a prospective, randomized open-label, 2 arm, 3-phase trial to compare the 48-weeks virological response of two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (drv/r) vs abacavir/lamivudine + raltegravir (ral) in antiretroviral therapy naive, hiv+ individuals presenting for care with cd4+ counts \< 200/mm3. 1.1 clinical objectives: primary objective: to compare the 48-week virological response to two different regimens containing abacavir/lamivudine (abacavir/lamivudine +darunavir/ritonavir (drv/r) vs abacavir/lamivudine + raltegravir (ral) in antiretroviral therapy naive, hiv+ individuals presenting for care with cd4+ counts \< 200/mm3. secondary objective: 1. to compare immunological response at 48 weeks; 2. to determine the safety and tolerability of the 2 regimens. 1.2 study population: 350 inpatients or outpatients will be randomized 1.3 outcome primary endpoint * proportion of patients with undetectable viremia (hiv rna\<50 copies/ml) after 48 weeks secondary endpoints(s) * change in cd4+ cell count from baseline through week 48 * time to virological rebound safety endpoints * incidence of adverse events (aes) * incidence of serious adverse events (saes) * discontinuations due to adverse events * incidence of grade 3 or 4 laboratory abnormalities. 1.4 study design multicentre, parallel group, randomised, open label, non-inferiority study 1.5 planned sample size: the planned sample size for this trial is 350 patients 1.6 treatment regimens: arm a: abacavir/lamivudine 1 tablet once a day + raltegravir 400 mg (1 tablet twice a day) arm b: abacavir/lamivudine 1 tablet once a day + ritonavir 100 mg + darunavir 800 mg once a day. all drugs have been approved for the treatment of hiv infection. administration: oral the study population will consist of 350 hiv-positive, hla b5701-negative patients. at baseline, patients will be randomized 1:1 to start abacavir/lamivudine plus either raltegravir or darunavir/ritonavir. randomization will be stratified on the basis of the screening cd4+ cell count (≤100 vs ≥100 cells/µl), to ensure balance across treatments groups 1.7 criteria for safety: adverse events and laboratory assessments. 1.8 statistical analysis: as this is a non-inferiority trial, we will calculate the difference in the proportions of patients experiencing the primary outcome in the two treatment arms and will calculate a 95% confidence interval for this. non-inferiority of the raltegravir arm will be demonstrated if the lower limit of the 95% confidence interval is greater than -12%. in case non-inferiority will be met, analyses for superiority will be performed.

Eligibility criteria:
inclusion criteria: 1. males or females (inpatients or outpatients) aged 18-64 years who are hiv-1 antibody seropositive, with a cd4 count \<200 cells/ul. 2. all patients should be antiretroviral-naive 3. all patients should be hla b57 or hla b5701 negative 4. patients must have an hiv rna level \<500,000 copies/ml 5. patients with an active opportunistic infection could be enrolled as long as this was diagnosed more than 2 weeks prior to screening. 6. patients must meet the following laboratory criteria. neutrophil count \> 1,000 cells/mm3 haemoglobin \> 9.0 grams/dl (men and women) platelet count ≥ 75,000 cells/mm3 alkaline phosphatase \< 3.0 the upper limit of normal alt and ast \< 3.9 times the upper limit of normal total bilirubin \< 1.5 times the upper limit of normal. 7. female patients of childbearing potential must be willing to use a reliable form of contraception, which will include a medically approved form of barrier contraception. 8. patients must be able to provide written consent to comply with study requirements. exclusion criteria: 1. patients with genotypic mutations for any of the study drugs. 2. patients with an opportunistic infection diagnosed in the 2 weeks prior to screening. 3. female patients who are pregnant or breastfeeding. 4. patients who are receiving any investigational drug or anti-neoplastic radiotherapy/chemotherapy other than local skin radiotherapy within 12 weeks before randomization. 5. patients with a current history of intravenous drug abuse, alcohol or substance abuse.

Keywords: late presenter naïve advanced hiv disease